Astragalus Polysaccharide Improves Myocardial Fibrosis in Hypertrophic Cardiomyopathy Through the TGF-β1/Smad3 Signal Pathway

Background: Myocardial fibrosis is a key pathological driver of Hypertrophic Cardiomyopathy (HCM), contributing to adverse remodeling and poor prognosis. The transforming growth factor-β1/Smad3 (TGF-β1/Smad3) signaling cascade plays a central role in fibrogenesis; however, effective antifibrotic therapies remain limited. Astragalus polysaccharide (APS), a bioactive constituent of Astragalus membranaceus, has demonstrated cardioprotective potential. Nevertheless, the mechanisms underlying its effects in HCM-associated fibrosis remain unknown. Methods: Pressure overload induced HCM was established in C57BL/6J mice using transverse aortic constriction (TAC), and animals were randomized to control, TAC, low-dose APS (50 mg/kg/day), or high-dose APS (100 mg/kg/day) groups. Cardiac function was evaluated by echocardiography, while myocardial hypertrophy and fibrosis were assessed by morphometry, Masson’s staining, and collagen I (Col-I) expression analysis. Parallel in vitro studies employed angiotensin II stimulated (Ang II-stimulated) H9C2 cardiomyocytes, with or without the TGF-β1/Smad3 agonist SRI-011381, to explore mechanistic pathways. Results: TAC induced marked cardiac dysfunction, ventricular dilation, and extensive fibrosis, accompanied by upregulation of TGF-β1, phosphorylated Smad3, and Col-I expression (all p < 0.05). APS treatment dose-dependently preserved systolic function, attenuated collagen deposition, and suppressed activation of the TGF-β1/Smad3 axis, with the strongest effects observed in the high-dose group. In vitro, APS significantly inhibited Ang II induced hypertrophy and fibrotic protein expression; these effects were abrogated by SRI-011381, confirming pathway specificity. Conclusions: APS exerts cardioprotective and antifibrotic effects in HCM by inhibiting the TGF-β1/Smad3 signaling pathway. These findings highlight APS as a promising therapeutic candidate for targeting myocardial fibrosis and improving outcomes in HCM.